Bosentan, one of the compounds disclosed in CA2071193 and its equivalent U.S. Pat. No. 5,292,740, belongs to an important class of sulfonamides having endothelin inhibiting activity useful in treatment of hypertension, ischemia, and related diseases.

U.S. Pat. No. 5,292,740 further discloses a process for preparation of bosentan comprising diethyl bromomalonate and guaiacol as the reactants. The final step of the process is the reaction of substituted pyrimidine monohalide derivative with ethylene glycol in the presence of sodium hydroxide to give bosentan. In this step, coupling of two molecules of pyrimidine monohalide derivative with one molecule of ethylene glycol generates undesirable impurities, such as the dimeric impurities, as the by-products. Multiple crystallization and purification steps are required to lower the amounts of these impurities. Also, the process requires use of excess of ethylene glycol which makes it costly and difficult to handle on industrial scale.
U.S. Pat. No. 6,136,971 describes an alternate process for the preparation of bosentan which uses monoprotected ethylene glycol. The process comprises reacting a substituted pyrimidine monohalide derivative with ethylene glycol mono t-butyl ether in the presence of sodium hydroxide in toluene to give a t-butyl ether derivative which is deprotected with formic acid in toluene to give a 2-(formyloxy)ethoxy derivative. Finally, removal of the formyl group by treatment with aqueous sodium hydroxide yields bosentan. The process requires additional steps of protection and deprotection of ethylene glycol that makes the process laborious and expensive.
In the processes of the prior art, the reaction of a substituted pyrimidine monohalide derivative with unprotected/protected ethylene glycol either generate undesirable impurities, for example, dimer impurities up to an amount of 10%, and thus require a number of purification and isolation steps to remove impurities or they require protection and deprotection of ethylene glycol which is time consuming and not feasible industrially.
Secondly, the essential feature of the reaction of substituted pyrimidine monohalide derivative with ethylene glycol is the use of a base, specifically a strong inorganic base, i.e., sodium hydroxide. It is found that the reaction does not proceed in the presence of an organic base, such as triethylamine or N-ethyldiisopropyl amine. The prior art indicates that the reaction proceeds only in the presence of a strong inorganic base. But, the use of a strong base produces undesirable impurities which affects the yield and purity of the product.
Therefore, there remains a need in the art for an improved process which is able to overcome the shortcomings of the prior art processes. Also, there is a need for a process that is simple for industrial scale up, and which requires fewer purification and isolation steps thereby obtaining the bosentan in good yield and purity.
Bosentan is marketed under the brand name Tracleer® by Actelion Pharmaceuticals. The active ingredient in Tracleer® is bosentan monohydrate which has a water content of about 3-5%.
Generally, an ideal candidate for any type of pharmaceutical formulation is an active ingredient which is non-hygroscopic in nature. The presence of any amount of moisture can lead to the formation of agglomerates, lumps, and impurities in any formulation. Thus, it is not always suitable to have an active ingredient having a high moisture content.